Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Presentation and Real-World Management of Giant Cell Arteritis (Artemis Study).

Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.

Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis.

Importance: In systemic sclerosis (SSc), to date, no study has precisely described the total number and fine distribution of telangiectases (TAs), their clinical association with the disease, and the biological mechanisms causing their development. Objectives: To describe the whole-body distribution of TAs and assess the association between the whole-body TA number and the characteristics of patients with SSc. Design, Setting, and Participants: A single-center, cross-sectional study was conducted between July 11, 2016, and March 15, 2017, at the National Referral Centre for Rare Systemic and Autoimmune Diseases in France. A population-based sample of 106 adults who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc were included; 8 patients who had previously received laser treatment for TAs were excluded. Main Outcomes and Measures: The number of TAs on the whole body (total and those >5 mm) and TA distribution in different areas were recorded. The association with clinical and biological data was studied using univariate and multivariate linear regression. Results: A total of 106 patients (83 [78.3%] women) were enrolled, including 12 with precapillary pulmonary hypertension (PH). Mean (SD) age was 60.6 (13.5) years. Telangiectasia distribution was 37.2% on the face, 33.2% on the upper limbs, including 26.4% on the hands, 28.1% on the trunk, including 17.1% for the upper part of the trunk, and 1.5% on the lower limbs. In analysis using the multivariate linear regression model, the whole-body TA number was independently associated with male sex (percentage change, 144.4%; 95% CI, 7.5% to 455.9%; P = .03), PH (162.8%; 95% CI, 5.6% to 553.8%; P = .04), history of pulmonary embolism (336.4%; 95% CI, 39.0% to 1270.1%; P = .01), glomerular filtration rate (-1.6%; 95% CI, -3.2% to -0.1% per 1-mL/min/1.73 m2 increase; P = .04), and soluble endoglin level (28.2%; 95% CI, 1.2% to 62.5% per 1-ng/mL increase; P = .04). Receiver operating characteristic analyses assessing the ability of TAs to identify the presence of PH revealed that the area under the curve was significant for the TA number on the whole body (0.77; 95% CI, 0.57 to 0.88), on the hands and face (0.81; 95% CI, 0.57 to 0.91), and on the hands (95% CI, 0.77; 95% CI, 0.57 to 0.89). Conclusions and Relevance: In the patients in this study with SSc, TAs were predominantly located on the face, hands, and the upper part of the trunk. Telangiectases appeared to be associated with vasculopathy features of SSc, particularly with PH and soluble endoglin levels.

Altered B lymphocyte homeostasis and functions in systemic sclerosis.

Beyond the production of autoantibodies, B-cells are thought to play a role in systemic sclerosis (SSc) by secreting proinflammatory/profibrotic cytokines. B-cells are a heterogeneous population with different subsets distinguished by their phenotypes and cytokine production. Data about B-cell subsets, cytokine production and intracellular pathways leading to this production are scarce in SSc. The aim of our study was to describe B-cell homeostasis, activation, proliferation, cytokine production in B-cells and serum and B-cell intracellular signaling pathways in SSc. We hypothezided that B-cell homeostasis and cytokine production were altered in SSc and could be explained by serum cytokine as well as by intracellular signaling pathway abnormalities. Forty SSc patients and 20 healthy controls (HC) were prospectively included. B-cell subsets were determined by flow cytometry using CD19, CD21, CD24, CD38, CD27, IgM and IgD. CD25, CD80, CD95, HLA-DR were used to assess B-cell activation. Intracellular production of IL-10 and IL-6 were assessed by flow cytometry after TLR9 and CD40 stimulation. IL-6, IL-10, Ki67, Bcl2 mRNA were quantified in B-cells. Cytokine production was also assessed in sera and supernatants of B-cell culture, using a multiplex approach. Signaling pathways were studied through phosphorylation of mTOR, ERK, STAT3, STAT5 using a flow cytometry approach. We found that SSc patients exhibited an altered peripheral blood B-cell subset distribution, with decreased memory B-cells but increased proportion of naive and CD21LoCD38Lo B-cell subsets. We observed an increased expression of activation markers (CD80, CD95, HLA-DR) on some B-cell subsets, mainly the memory B-cells. Secretion of IL-6, BAFF and CXCL13 were increased in SSc sera. There was no correlation between the peripheral blood B-cell subsets and the serum concentrations of these cytokines. After stimulation, we observed a lower proportion of IL-10 and IL-6 producing B-cells in SSc. Finally, we observed a significant decrease of mTOR phosphorylation in SSc patient B-cells. In conclusion, we observed an altered B-cell homeostasis in SSc patients compared to HC. Memory B-cells were both decreased and activated in patients. IL-10 producing B-cells were decreased in SSc. This decrease was associated with an alteration of mTOR phosphorylation in B-cells. Conversely, there was no correlation between serum cytokine profile and B-cell homeostasis alterations.